Category: health

disgraceful discourse on the anti-dengue drug

i get asked why i bother to blog again and again on ActRx TriAct when no one seems to be reading, much less agreeing; mostly, the comments only echo, insist on, what kill-the-cocktail proponents feed an unthinking mediocre media.

meron naman akong readers, heh, or so my site stats tell me, and dr. stuart and i have been receiving email thanking us for the posts and the research and wishing that mainstream media would pick them up, publish them as well, so the public may know.  yeah, we wish.

but even if i had just a handful of readers, or even if no one agreed with the sentiments expressed herein, i would continue to blog, if only for the record.  i would continue to share my thoughts and reactions on an issue such as this that has national and worldwide significance.  dengue is a global public health concern, after all, and let it not be said, now and in the future, that pinoys, one and all, sat back and allowed the killing of a promising anti-dengue cocktail without question or resistance.

which is also to say that it is dismaying, nay, disturbing, nay, scandalizing! that the public discourse is so one-sided.  except for dr. tony leachon, speaking for the philippine college of physicians and the philippine medical association, and dr. sylvia claudio in her online column – both pro-garin, it would seem — we are not hearing any dissent from the medical community.  no doubt there are dissenters, but unfortunately they choose to not make public their informed opinions (along with their identities), they choose to not engage in, contribute to, an exchange of  expert views, whether for or against.  ask them why, and they’ll invoke the politics, the dirty politics; they’d rather not get involved.

but surely the good doctors know that their silence has political repercussions, too, giving the impression that they’re all okay (as in, all right) with acting DOH sec garin’s godawful decision to stop the ActRx TriAct clinical trials?

yeah, the devil is in the politics.*  and on this blog, we dare confront that devil.

Dr. Stuart:  I received anonymous emails with links to articles on the position of the Philippine Medical Association (PMA) and the Philippine College of Physicians (PCP), in support of the cancellation of the expanded clinical trials of the anti-dengue drug, ActRx TriAct. One was accompanied by a link to the WMA (World Medical Association)’s Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects.

What the media reported on the PMA POSITION was a nitpicking criticism, full of text extracts from Dr. Calimag, without even the briefest elucidation on the censured design and analysis flaws.

In contrast, The WMA DECLARATION OF HELSINKI: ETHICAL PRINCIPLES FOR MEDICAL REASEARCH INVOLVING HUMAN SUBJECTS was an interesting read. I wondered which of the 37 articles the ActRx TriAct study violated. I likewise wondered if maybe it was sent in support of the ActRx TriAct study.

The last article was especially compelling: Unproven Interventions in Clinical Practice — “…where proven interventions do not exist or other known interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legal representative, MAY USE AN UNPROVEN INTERVENTION IF IN THE PHYSICAN’S JUDGMENT IT OFFERS HOPE OF SAVING LIFE, RE-ESTABLISHING HEALTH OR ALLEVIATING SUFFERING.” Compelling — because it advocates the use of the medicine for compassionate use.

I don’t want to belabor the fact. The components of the ActRx TriAct anti-dengue therapy are old drugs, being repurposed or repositioned for new uses. Repositioning or repurposing drugs is one way of significantly shortening the process of drug studies and trials. Yet, criticisms continue to express incredulity on why the ActRx TriAct therapy did not take the usual 12 to 14 years of new drug development.

The PCP POSITION also slammed the people behind the clinical trial for including some children as subjects. Why are doctors so horrified or against testing the efficacy of the treatment on children? Ladies and gentlemen, it is the children who are most vulnerable, it is in the children’s sector where most fatalities are found in a 2011 study. From January to September, there were a total of 86,662 cases, with 65,000 (74%) occurring in all confirmed cases. 36% of these occurred in children aged 1-9 years, resulting in 265 deaths, representing 60% of deaths due to dengue in 2011.

CRAP?  There was also a public status on facebook posted by Dr. Claudio, that “the science supporting Ona’s anti-dengue miracle drug is crap.” In the course of public discourse, that the best argument a doctor in her position can offer is that the study is “crap,” is sad, unprofessional, disreputable, and downright juvenile. The study is crap!—and that’s it? We take her word for it? We deserve better than that. She should not have called a study “crap” based on reports she is privy to but she is not willing to divulge. Such criticism is crappier than crap.

The medical voices or the guardians of truth charged with informing the public is burdened with the responsibility of providing explanatory answers, not silently agreeing to pronouncements of “crap.”

We need a clear judgment and resolution on this controversial matter from a really independent scientific review board — if that is at all possible — not rantings from the bully pulpit or DOH press releases dutifully published by kowtowing media, repeating, ad nauseam, pronouncements from on high without looking deeper into or researching the issues.

GAME OVER?  But is it all moot now? Has the circus left town? Dr. Ona has resigned, silenced, lips politically zipped? The pneumonia vaccine issue abandoned to die a quiet death? The anti-dengue drug vilified as crap? The study criticized as unethical, diagnostically inaccurate, no endorsements, dubious paper trails, poorly designed, flawed data analysis, blah blah blah? Were these a fagot of separate political issues—of demolition, positioning, wheeling-dealing, and a clashing of government egos—really meant to get Ona out of the picture?

Or is this partly issuing from the great disdain by many in the medical community of anything that has to do with alternative medicine? Remember, many of the medicines that grace the pharmaceutical landscape are plant derived, and many more are waiting to be discovered, many a lot safer, without the toxicities of synthetic pharmaceuticals.

In the ActRx TriAct study of 290 patients — 145 received the drug treatment, 145 did not — there were no deaths in both groups of patients. The PCP concludes that because no one died in the 145 who didn’t take the drug, the “experimental drug added nothing in preventing deaths.” This is a valid scientific conclusion? Or just a position intent on seeing the cup half empty rather than half full.

In different studies, dengue deaths ranged from one for every 185 to 250 cases. In the ActRx TriAct study of 290 patients (145 with treatment, 145 without), taking the optimist position, the absence of death might suggest the benefit of prevention of at least one fatality.

Calimag also said: “the lack of adverse events in a small sample size is not conclusive evidence of the absence of harm.” Taking the optimist position, the absence of adverse effects might suggest the absence of toxicity — three drug components that have already undergone extensive toxicity evaluation — and the absence of deaths, albeit a small sample size, should support further expanded study and testing, especially in the many provinces that have attained malaria-free status.

THE CAT IS OUT OF THE BAG.  Even here in the boondocks, a local alternative healer has asked me about it. In places like these, what is to keep the local healers from accessing the separate components of the drugs for the occasional desperate families seeking any possible treatment for dengue stricken family members?

Is the study dead? I hope not—because the anti-dengue drug treatment has NOT been debunked. And calling it “crap” doesn’t kill it. Perhaps, dissenting voices from the medical community might still surface and dare to disagree with the powers that be, provide a badly needed and audible point of view.

If it is a bad study, tweaked or falsified, or in the end, proven as crap, I’ll be glad to help pull the trigger and kill it. BUT if the potential to save lives still exists, the testing and expanded use must be allowed to go forward. This year, from January to September 2014, there have been about 60,000 reported cases of dengue in the Philippines, with about 242 deaths (4 deaths for every 1,000 cases). These numbers cry out.

What a shame if in the end ActRx TriAct is taken elsewhere, and the drug is shown to work.

my pet theory is, the demolition job on ona and ActRx TriAct is in aid of that dengue vaccine for which a huge pharmaceutical company has spent $1.5 B on research and development, soon to be out in the market.  as i’ve blogged before, we could use both ActRx TriAct AND a dengue vaccine.  dr. stuart tells of the vaccine’s limitations here.

and if you’ve read this far, good for you, i saved some juicy tidbits for last.  over the holidays, different grapevines were buzzing with anti-garin stories: how she wants the post so badly, sorry na lang si ona, and how she’s not even qualified for such a high post — she’s more a politician daw than a physician, much less, a scientist (check out her wikipedia profile).

but the juiciest story, a sweet stab of sarcasm from ona himself, came via inquirer’s christmas day report, Ona: Loss of Aquino’s confidence prompted me to quit

When asked about his relationship with the acting health secretary, Ona said he thought it was “very ideal.’’

… “My personal things were brought to my house even before I officially announced my resignation and there’s only one person in DOH who could make such order,’’ Ona said.

whew, what a game she plays.  this is the same aquino-appointed acting DOH sec who brazenly disobeyed the quarantine rules imposed on families of travellers from ebola-stricken countries, the very same one, still unmasked, whom our senators welcomed to their august halls with beso-besos to boot.

the anarchy proceeds apace.  in the highest places yet.


* “The devil is in the politics” is how i ended the book Revolutionary Routes: Five stories of incarceration, exile, murder, and betrayal in Tayabas province, 1891-1980 (2011)

So who wants Dr. Ona’s post?

By Katrina S.S.

Second of two parts

Clinical trials and the anti-dengue cocktail

But the bigger story is about the anti-dengue cocktail that is ActRx Triact, the clinical trials for which were started in 2012, as ordered by Dr. Ona. Acting Health Secretary Janette Garin stopped the clinical trials the moment she stepped in, declaring that it had “no legal basis” as it had yet to be approved by the Food and Drug Administration (FDA). At that point the Philippine Council for Health Research and Development (PCHRD) had questioned the soundness of the science behind the clinical trials. Since then the Philippine Medical Association (PMA), the Philippine Society for Microbiology and Infectious Diseases (PSMID), and members of the Philippine College of Physicians (PCP) have thrown their support behind Garin’s decision to stop the trials. These organizations question the science and ethics behind the clinical trials, and assert the dangers it poses to the public’s health. Dr. Sylvia Claudio has called the science behind the clinical trials “crap,” saying that it is “a medical horror story.”

Read on…

In Defense of the Anti-Dengue Cocktail

By G. U. Stuart, MD

I became aware of the ActRx TriAct controversy only after the the study was pulled or suspended by the powers that be. It wasn’t clear why, and it still isn’t. There was no outright allegation that the researchers tweaked data or fabricated results—that would certainly have justified killing the study. Instead, the DOH and a complicit media have been spewing out allegations, discrediting, questioning the validity of the study and the verity of its conclusions. Non-compliance and deficiency issues? Were there application issues? Conditions that were not met? Design flaws? Ethical issues? Monitoring failures? Statistical or methodological problems? Why was it pulled only after the Phase III results were released? Is it all “politics,” as some suggest?  In the absence of clear evidence of a bad study, I chose to give the ActRx TriAct cocktail the benefit of the doubt.

This is not a defense of Ona. I don’t know Ona from Adam. This is a defense of the public’s right to know, of the right of patients to access a drug that could potentially prevent deaths from a disease that claims thousands of fatalities a year.

There continues to be a dearth of supportive or explanatory documents relating to the ActRx TriAct phase III clinical trial study. My search always dead-ends at the ActRx website. Even if the complete study were available, I would not have the acumen to comb through the scientific minutiae. What is urgently needed is an independent review board to look at the study—to document its faults and justify the suspension, or to disprove the criticisms and dismiss the doubts.

The criticisms have been mostly negative—that the studies did not go through the usual preclinical trials or were dubiously sped through some clinical trial phases; that it is monotherapy treatment because it uses two artemisinin derivatives; that berberine, a plant derivative, should not be used as a third component; that berberine, for lack of scientific studies, was not approved by the FDA; that experts say the combination of the three drugs poses sides effects and that their use in clinical trials poses a “clear and present danger” to public health; that there is no legal basis for the study; and, horrors, that no other studies on ActRx TriaAct have been done or are being conducted elsewhere in the world.


The main components of ActRx TriAct are artemether and artesunate, drugs long ago studied and approved for use in malaria. Both have gone through the necessary preclinical studies. When repurposing or repositioning drugs—finding new uses for old drugs—the studies are usually allowed to skip some of the phases, certainly, preclinical trials that are done in animals to test for toxicity and pharmacokinetics. Possibly, too, it was fast-tracked and sped through Phase 0 and Phase 1 studies, getting to clinical trials faster.

Drug Repurposing or Repositioning: Drug repositioning is the process whereby a drug that is patented for treating a particular disease is discovered to be useful in treating a second disease, and developed further for that purpose. Simply said, it is a process of finding new use for an existing drug. As mentioned above, this is the case with artemether and artesunate—old drugs already approved for malaria, already tested in humans with known information on pharmacology, formulation and potential toxicity—now being tested as potential dengue treatment, allowing the new therapy to be ready for clinical trials early, hoping for a speedy review and integration into health care. Hopefully, this answers PCHRD’s concern of “deficiency”—that the study lacks scientific justification for use of artemether and artesunate for dengue therapy.

Cocktail Components

Artesunate: Oral artesunate was probably chosen for ease of administration, with a longer half-life (20-45 minutes) and higher bioavailability of DHA, dihydroartemisnin, its active metabolite (>80%), half life of 0.5 to 1.5 hours—values not achieved by intramuscular and intravenous administration, and without the ease of oral administration.

Artemether: Artemether has been available in the tablet, capsule, and injectable formulations. A study on sublingual spray formulation showed twice the bioavailability—1.7 to 2.2 times more absorption as a sublingual spray compared to oral tablet formulation. The sublingual route also bypasses the first-pass liver metabolism.

Berberine: Berberine is an alkaloid extracted from various plants. (See below). It has been studied extensively. Its mechanisms of action are as varied as the many conditions it is used as supplement for.

Patent Pending

There is a patent pending on the ActRx TriAct cocktail, a two-day regimen, composed of artemether sublingual spray, artesunate and berberine tablets. Possibly, the combination use of artemether with artesunate, where the drugs might act in complementary or synergistic manner, together with the addition of berberine, is a way to get exclusivity—via an MoU (method of use) patent protection—for old drugs in a new formulation with a unique sublingual delivery system for artemether.


There is much criticism that using derivatives from the same plant constitutes monotherapy. True, both artemether and artesunate are derivatives of artemisinin, a peroxide lactone isolated from the antimalarial plant, Artemesia annua (sweet wormwood). The plant has been used in many traditional systems of medicine, for at least 2000 years in China. Artemether is a methyl ester derivative, while artesunate is a semisynthetic analogue derivative. Although both are artemisinin derivatives—artemether, sublingually; artesunate, orally—they may differ in their potencies with the peroxide mechanisms, half life and elimination time. Perhaps, the combination was based on peaks, half-life and elimination time, that give a synergistic effect, or delay or prevent resistance? This is a personal conjecture. I would like to know the ActRx Triact researchers’ rationale for the use of the combination.


• The inclusion of berberine, a plant material, has also raised the hackles of some. But the landscape of medical therapies is rich with plant-derived pharmaceuticals. Like artemisinin, which is derived from the antimalarial plant Artemesia annua, berberine,  the third component of the Actrx Triact cocktail, is an isoquinoline alkaloid of protoberberine, which is found in many plants and has been used in many traditional medical systems for hundreds of years.

• In search of an herbal medicinal source for dengue cure, a 2011 study investigated the in-vitro anti-dengue activity of ten Thai medicinal plants; four plants viz. Rhizophora aciculate, Flagellaria india, Cladogynos orientalis, and Houttuynia cordite, showed significant effect on the dengue virus in-vitro and suggested potential sources for the development of an anti-DENV drug. Herbal Antivirals: Natural Remedies for Emerging & Resistant Viral Infections by Stephen Harrod Buhner lists 29 plants that have shown anti-dengue activity; four, maybe more, of them yield berberine.  Other reviews list berberine-bearing plants used in botanical medical practice: Goldenseal (Hydrastis canadensis), Oregon grape (Berberis aquifolium) Barberry (Berberia vulgarism) and Chinese Goldthread (Coptis chinensis), and two berberine-containing plants popular in Chinese medicine, Phellodendron chinense and Phellodendron amurese.


“For lack of scientific studies on berberine, the Food and Drug Administration did not give it certification for sale in the Philippines.” Huh? Berberine has been much studied—over a third of the 2,800 studies on berberine listed on PubMed, were published in the last 5 years. The studies suggest a wide range of clinical applications—from cholesterol lowering, anti-inflammatory, antimicrobial, anti-diabetic effects to benefits for cardiovascular and neurodegenerative afflictions.

• Berbrine is an over-the-counter supplement, considered by some studies as a supplement with some effects comparable to pharmaceuticals. Its standard dose is 900-2000 mg a day in 3 or 4 divided doses. A recent study reported a concern for long-term use and a tendency to accumulate in the CNS with potential neurotoxicity. What dosages are used and what risks are entailed in a two-dose ActRx TriAct cocktail protocol should be answered by the ActRx TriAct researchers.


What side effects are the “experts” attributing to the ActRx TriAct treatment? Artemether and artesunate are two drugs extensively studied and used in the treatment of malaria. Berberine is a supplement in use for hundreds of years in many traditional systems, with a known good safety profile, especially for short-term use. “Clear and present danger ” to public health? Huh?


The DOH says the controversial ActRx TriAct has not been registered with the FDA, and that the study which started in 2012 should not have happened in the first place. Is this true? By whose authority and edict was it allowed to continue? Why did they wait so long before terminating it? Were people threatened by the reported beneficial study results? What political power plays are at work? Does the non-registration mistake totally nullify the study?


Criticism was also made that no other studies on ActRx TriAct have been done or is being done elsewhere in the world. Does the criticism imply that our scientists cannot or should not pursue original investigative studies? That is an insult, an affront, to the Philippine scientific research community.

The criticisms have remained unanswered. I am surprised and dismayed by the silence from Ona’s side, from the doctors who were involved with the actual clinical study, and from others somewhere out there in the medical community who must have a dissenting opinion to what seems to be one-sided multiple rants against Ona’s work.

Also, let us hear from those on the Garin side, who according to a post by Jarius Bondoc, “were pacified by Garin’s move—regulators, researchers, ethicists, and field doctors who, documents show, resist the remedy.” It would be most enlightening to hear from this august array of professionals what aspects of the study or remedy they resisted and why.

The Promise of a Vaccine Tomorrow, The Need for a Treatment Today

Dengue vaccine trials are being done. The experimental Dengue vaccine developed by Sanofi showed to be about 60% effective in the second large clinical trial, a slight improvement from the 56.5 percent reduction in the first trial. The scientific adviser to the Dengue Vaccine Initiative admits it’s not anywhere close to the 90s they hoped for. The vaccine was found to be more effective in people previously exposed to dengue. There are four serotypes, with lifelong immunity gained only for the specific infecting serotype—making the vaccine useful in endemic areas where people are often exposed more than once. Also, while providing 60-90% efficacy against dengue virus 1, 3, and 4, efficacy was lacking (42%) against DENV serotype 2 which accounts for almost 60% of all virologically confirmed dengue episodes. Also, in the first trial, the vaccine was found less effective in younger children, the population most vulnerable to the disease.  The early availability of the vaccine will also be limited. No matter these early limitations, a vaccine that may reduce the number of cases by half and hospitalizations by 80 percent represents a big advance.  Sanofi plans to apply for approvals in the first quarter of 2015, with sales in the 4th quarter in priority countries of Mexico, Brazil and Columbia, and possibly Singapore and Malaysia.

While the vaccine shows promise, there will still be a significant number of those vaccinated who will still contract dengue. Also, there will be many who will refuse vaccination, and many who will not be reached by vaccination programs. The WHO estimates that 2.5 billion people are at risk annually for dengue infections. Between 50 million and 100 million contract the disease each year; newer estimates suggest a number closer to 400 million. Thousands of deaths are still predictable.

Drug therapy is needed. For now there is none. The Actrx Triact cocktail presents as a potential anti-dengue drug therapy for that group of patients diagnosed with severe dengue where the risk of fatalities are high. And while the WHO has warned of the dangers of drug resistance in areas where both malaria and dengue are coendemic, there are 23 designated malaria-free provinces in the Philippines. They present testing grounds to evaluate the efficacy of the anti-dengue therapy: Cebu City, designated malaria free, topped the list with 3,081 cases of dengue with 12 deaths; Iloilo, also designated malaria-free, reported a 71% surge in dengue cases. Aklan, also malaria-free, has seen an increase of 75%, up 1,340 cases compared to 763 last year. The data collected from these malaria-free testing grounds can potentially lay the groundwork for more widespread testing and use of the cocktail.

The conflicts surrounding ActRx TriAct should be urgently resolved. Politics should be pushed aside. Let us hear from the experts, the field doctors, and ethicists, without masks of anonymity. I have heard that people in the know are afraid to talk. I have been forewarned, the issue is dead. That the powers that be have already decided.

I hope not. Yet that is what I sense from reading the press releases—a demolition stonewalling blackballing campaign. A rain of criticisms, charges and insinuations—everthing from A to Y. But there’s the Z question: Does the drug work?

It is too important a drug to die a political death. Either debunk it or release it back into testing and use. And until or unless the treatment benefit is utterly and completely debunked, dengue patients who are not involved in the clinical trials but are seriously ill should be allowed the ActRx TriAct cocktail treatment by access through compassionate use.


my son joel was going on 4 in 1977 when he came home from pre-school running a slight fever. lagnat-laki lang, i hoped, and started giving him tempra.  when the fever kept coming back and going up, i took him to his pediatrician who said to continue with the meds plus lots of water. but over the next day the fever was up to 39.5, and creeping closer and closer to 40; he was barely eating, and mostly throwing up the medicine and the little food i could force, beg, him to swallow.  freaking out, we brought him to Lourdes Hospital’s ER where the residents took one look at his inner arm, near the joint…pointed to tiny red dots i hadn’t noticed (or maybe they had just come out), and at once proceeded to draw blood for lab tests while also inserting an IV needle.  he struggled and cried and screamed, of course; i could only help hold him down.  H-fever, i.e, hemorrhagic fever, also known as dengue, was the diagnosis.  he needed transfusions, 3 bags of platelets.  it was nerve-wracking.  what if we didn’t bring him in when we did?

later, whenever i would hear news of sudden deaths by dengue, i’d remember, always, how swiftly the virus multiplies to a critical point and, lacking medical intervention, simply takes over and kills.  so, truly, the october 20 news report of a “breakthrough drug” vs. dengue, endorsed by dr. enrique ona, the DOH secretary, no less, was fantastic news for public health.

Ona said that “on March 15, Preferred and Proven Therapies Inc., ActRx Foundation and ActRx Operational Group, together with PITAHC and San Lazaro Hospital for Infectious Diseases medical research team, presented a report showing the remarkable success of the clinical trials conducted at San Lazaro Hospital on ActRx TriAct, a patented herbal-based combination of Artesunate, Berberine and Artemether as therapy treatment for dengue.”

alas, just eight (8) days after that october 20 public announcement, dr. ona went on leave, ostensibly over a pneumonia-vaccine controversy.  but suddenly there were also reports of dr. ona being in trouble over the anti-dengue drug.  i sent links on the subject to my brother butch for a medical opinion; a few days later he sent me this: Dengue, Drugs, Death and Politics, which i posted in my november 30 entry, in defense of dr. ona.

to our surprise, comments were largely negative, basically harping on the danger posed to public health by ona’s endorsement of a mysterious drug of unproven safety and efficacy.  since then, we have been combing the Web for additional information, looking for something from the ona camp that would debunk the allegations, point by point.  instead we kept coming up against blank walls, and even more questions than answers.

consider, for instance, this timeline: september 24, ona issued DOH order no. 2014-016 authorizing the use of ActRx TriAct in the treatment of dengue cases. however, we do not hear about this wonderful news until almost a month later, on october 20.  *bakit kaya*  and then just 8 days later, on october 28 he goes on a month-long leave; dr. janet garin is named acting DOH secretary.  november 14, garin suspends the anti-dengue drug. however, we do not hear about this “welcome”news until December 1.  *bakit kaya*  and then december 2, from right field, came news of a promising dengue vaccine, aha!  can this be WHY the demolition job on ona and ActRx TriAct?  but we could use both a vaccine AND an anti-dengue therapy treatment!

and we sure could use a critical and perspicacious media who would know to ask around and ferret out the facts vs. what seems to be black propaganda meant to stop ActRx TriAct in its tracks.  like, i’ve been waiting to read something from senator heherson alvarez’s hexilon (CEO of Preferred and Proven Therapies, Inc.) that would elaborate on the success story of this anti-dengue treatment beyond the few soundbites in a tv news report.  where are our investigative journalists when we need them?